Inspra (Eplerenone): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Inspra

INSPRA contains eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor.

Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C₂₄H₃₀O₆ and it has a molecular weight of 414.50. The structural formula of eplerenone is represented below:

Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.

INSPRA tablets for oral administration contain 25 mg or 50 mg of eplerenone and the following inactive ingredients: lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, titanium dioxide, polyethylene glycol, polysorbate 80, and iron oxide yellow and iron oxide red.

Uses for Inspra

Heart Failure Post-Myocardial Infarction

INSPRA is indicated to improve survival of stablepatients with symptomatic heart failure with reduced ejection fraction(≤40%) (HFrEF) after an acute myocardial infarction (MI).

Hypertension

INSPRA is indicated for the treatment of hypertension, tolower blood pressure. Lowering blood pressure reduces the risk of fatal andnonfatal cardiovascular (CV) events, primarily strokes and MI. These benefitshave been seen in controlled trials of antihypertensive drugs from a widevariety of pharmacologic classes.

Control of high blood pressure should be part ofcomprehensive CV risk management, including, as appropriate, lipid control,diabetes management, antithrombotic therapy, smoking cessation, exercise, andlimited sodium intake. Many patients will require more than one drug to achieveblood pressure goals. For specific advice on goals and management, seepublished guidelines, such as those of the National High Blood PressureEducation Program’s Joint National Committee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety ofpharmacologic classes and with different mechanisms of action, have been shownin randomized controlled trials to reduce CV morbidity and mortality, and it canbe concluded that it is blood pressure reduction, and not some otherpharmacologic property of the drugs, that is largely responsible for thosebenefits. The largest and most consistent CV outcome benefit has been areduction in the risk of stroke, but reductions in MI and CV mortality alsohave been seen regularly.

Elevated systolic or diastolic pressure causes increasedCV risk, and the absolute risk increase per mmHg is greater at higher bloodpressures, so that even modest reductions of severe hypertension can providesubstantial benefit. Relative risk reduction from blood pressure reduction issimilar across populations with varying absolute risk, so the absolute benefitis greater in patients who are at higher risk independent of their hypertension(for example, patients with diabetes or hyperlipidemia), and such patientswould be expected to benefit from more aggressive treatment to a lower bloodpressure goal.

Some antihypertensive drugs have smaller blood pressureeffects (as monotherapy) in black patients, and many antihypertensive drugshave additional approved indications and effects (e.g., on angina, heartfailure, or diabetic kidney disease). These considerations may guide selectionof therapy.

INSPRA may be used alone or in combination with otherantihypertensive agents.

Dosage for Inspra

Heart Failure Post-Myocardial Infarction

Initiate treatment at 25 mg once daily and titrate to therecommended dose of 50 mg once daily, preferably within 4 weeks as tolerated bythe patient.

Once treatment with INSPRA has begun, adjust the dosebased on the serum potassium level as shown in Table 1.

Table 1: Dose Adjustment in Heart Failure Post-MI

Hypertension

The recommended starting dose of INSPRA is 50 mgadministered once daily. The full therapeutic effect of INSPRA is apparentwithin 4 weeks. For patients with an inadequate blood pressure response to 50mg once daily increase the dosage of INSPRA to 50 mg twice daily. Higherdosages of INSPRA are not recommended because they have no greater effect onblood pressure than 100 mg and are associated with an increased risk ofhyperkalemia [see Clinical Studies].

Recommended Monitoring

Measure serum potassium before initiating INSPRA therapy,within the first week, and at one month after the start of treatment or doseadjustment. Assess serum potassium periodically thereafter.

Check serum potassium and serum creatinine within 3-7days of a patient initating a moderate CYP3A inhibitor ACE inhibitors,angiotensin-II blockers or non-steroidal-anti-inflammatories.

Dose Modification For Use With Moderate CYP3A Inhibitors

In post-MI HFrEF patients receiving a moderate CYP3Ainhibitor (e.g., erythromycin, saquinavir, verapamil, and fluconazole), do notexceed 25 mg once daily. In patients with hypertension receiving a moderateCYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressureresponse, dosing may be increased to a maximum of 25 mg twice daily [seeDRUG INTERACTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

• 25 mg tablets: yellow diamond biconvex film-coated tablets debossed with Pfizer on one side and NSR over 25 on the other
• 50 mg tablets: yellow diamond biconvex film-coated tablets debossed with Pfizer on one side and NSR over 50 on the other

Storage And Handling

INSPRA Tablets are yellow, diamond biconvex, andfilm-coated. They are debossed with Pfizer on one side. They are supplied asfollows:

Abbreviation: NA=not applicable.

Store at 25°C (77°F); excursions permitted to 15–30°C(59–86°F) [See USP Controlled Room Temperature].

Distributed by: G.D. Searle LLC, Division of Pfizer Inc.,NY, NY 10017. Revised: May 2018

Side Effects for Inspra

The following adverse reactions are discussed in greaterdetail in other sections of the labeling:

• Hyperkalemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed in the clinical trials of adrug cannot be directly compared to rates in clinical trials of another drugand may not reflect the rates observed in practice.

Heart Failure Post-Myocardial Infarction

In EPHESUS, safety was evaluated in 3307 patients treatedwith INSPRA and 3301 placebo-treated patients. The overall incidence of adverseevents reported with INSPRA (78.9%) was similar to placebo (79.5%). Adverseevents occurred at a similar rate regardless of age, gender, or race. Patientsdiscontinued treatment due to an adverse event at similar rates in eithertreatment group (4.4% INSPRA vs. 4.3% placebo), with the most common reasonsfor discontinuation being hyperkalemia, MI, and abnormal renal function.

Adverse reactions that occurred more frequently inpatients treated with INSPRA than placebo were hyperkalemia (3.4% vs. 2.0%) andincreased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia orabnormal renal function were less than 1.0% in both groups.

Hypertension

INSPRA has been evaluated for safety in 3091 patientstreated for hypertension. A total of 690 patients were treated for over 6months and 106 patients were treated for over 1 year.

In placebo-controlled studies, the overall rates ofadverse events were 47% with INSPRA and 45% with placebo. Adverse eventsoccurred at a similar rate regardless of age, gender, or race. Therapy wasdiscontinued due to an adverse event in 3% of patients treated with INSPRA and3% of patients given placebo. The most common reasons for discontinuation ofINSPRA were headache, dizziness, angina pectoris/MI, and increased GGT.

Gynecomastia and abnormal vagin*l bleeding were reportedwith INSPRA but not with placebo. The rates increased with increasing durationof therapy.

Postmarketing Experience

The following adverse reactions have been identifiedduring postapproval use of INSPRA. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible toreliably estimate their frequency or establish a causal relationship to drugexposure. Skin: angioneurotic edema, rash

Clinical Laboratory Test Findings

Heart Failure Post-Myocardial Infarction

Creatinine

Increases of more than 0.5 mg/dL were reported for 6.5%of patients administered INSPRA and for 4.9% of placebo-treated patients.

Potassium

In EPHESUS [see Clinical Studies], the frequenciesof patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or≥6.0 mEq/L) receiving INSPRA compared with placebo are displayed in Table2.

Table 2: Hypokalemia (<3.5 mEq/L) or Hyperkalemia(>5.5 or ≥6.0 mEq/L) in EPHESUS

Rates of hyperkalemia increased with decreasing renalfunction.

Table 3: Rates of Hyperkalemia ( >5.5 mEq/L) inEPHESUS by Baseline Creatinine Clearance*

The rates of hyperkalemia in EPHESUS in the INSPRAtreated group vs. placebo were increased in patients with proteinuria (16% vs11%), diabetes (18% vs. 13%) or both (26% vs. 16%).

Hypertension

Potassium

In placebo-controlled fixed-dose studies, the meanincreases in serum potassium were dose-related and are shown in Table 4 alongwith the frequencies of values >5.5 mEq/L.

Table 4: Increases in Serum Potassium in thePlacebo-Controlled, Fixed-Dose Hypertension Studies of INSPRA

Drug Interactions for Inspra

CYP3A Inhibitors

Eplerenone metabolism is predominantly mediated viaCYP3A. Do not use INSPRA with drugs that are strong inhibitors of CYP3A [see CONTRAINDICATIONSand CLINICAL PHARMACOLOGY].

In post-MI HFrEF patients taking a moderate CYP3Ainhibitor, do not exceed 25 mg once daily. In patients with hypertension takinga moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate bloodpressure response, dosing may be increased to a maximum of 25 mg twice daily [seeDOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

ACE Inhibitors And Angiotensin II Receptor Antagonists

The risk of hyperkalaemia increase when eplerenone isused in combination with an ACE inhibitor and/or an ARB. A close monitoring ofserum potassium and renal function is recommended, especially in patients atrisk for impaired renal function, e.g., the elderly [see WARNINGS ANDPRECAUTIONS].

Lithium

A drug interaction study of eplerenone with lithium hasnot been conducted. Lithium toxicity has been reported in patients receivinglithium concomitantly with diuretics and ACE inhibitors. Serum lithium levelsshould be monitored frequently if INSPRA is administered concomitantly withlithium.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of eplerenone with an NSAID hasnot been conducted. The administration of other potassium-sparingantihypertensives with NSAIDs has been shown to reduce the antihypertensiveeffect in some patients and result in severe hyperkalemia in patients withimpaired renal function. Therefore, when INSPRA and NSAIDs are usedconcomitantly, monitor blood pressure and serum potassium levels.

Warnings for Inspra

Included as part of the PRECAUTIONS section.

Precautions for Inspra

Hyperkalemia

The risk of hyperkalemia is higher in patients withimpaired renal function, proteinuria, diabetes and those concomitantly treatedwith ACEs, ARBs, NSAIDs and moderate CYP3A inhibitors. Minimize the risk ofhyperkalemia with proper patient selection and monitoring [see DOSAGE ANDADMINISTRATION, CONTRAINDICATIONS, ADVERSE REACTIONS, and DRUGINTERACTIONS]. Monitor patients for the development of hyperkalemia untilthe effect of INSPRA is established. Patients who develop hyperkalemia (5.5-5.9mEq/L) may continue INSPRA therapy with proper dose adjustment. Dose reductiondecreases potassium levels. Patients on moderate CYP3A inhibitors that cannotbe avoided should have their dose of eplerenone reduced [see DRUGINTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Eplerenone was non-genotoxic in a battery of assaysincluding in vitro bacterial mutagenesis (Ames test in Salmonella spp.and E. Coli), in vitro mammalian cell mutagenesis (mouse lymphomacells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivorat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNAsynthesis in rat liver.

There was no drug-related tumor response in heterozygousP53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day(systemic AUC exposures up to 9 times the exposure in humans receiving the 100mg/day therapeutic dose). Statistically significant increases in benign thyroidtumors were observed after 2 years in both male and female rats whenadministered eplerenone 250 mg/kg/day (highest dose tested) and in male ratsonly at 75 mg/kg/day. These dosages provided systemic AUC exposuresapproximately 2 to 12 times higher than the average human therapeutic exposureat 100 mg/day. Repeat dose administration of eplerenone to rats increases thehepatic conjugation and clearance of thyroxin, which results in increasedlevels of TSH by a compensatory mechanism. Drugs that have produced thyroidtumors by this rodent-specific mechanism have not shown a similar effect inhumans.

Male rats treated with eplerenone at 1000 mg/kg/day for10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) haddecreased weights of seminal vesicles and epididymides and slightly decreasedfertility. Dogs administered eplerenone at dosages of 15 mg/kg/day and higher(AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-relatedprostate atrophy. The prostate atrophy was reversible after daily treatment for1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline inlibido, sexual performance, or sem*n quality. Testicular weight and histologywere not affected by eplerenone in any test animal species at any dosage.

Use In Specific Populations

Pregnancy

Risk Summary

The available data from published case reports oneplerenone use during pregnancy are insufficient to establish a drug-associatedrisk of major birth defects, miscarriage, adverse maternal or fetal outcomes (seeClinical Considerations). In animal studies, no adverse developmentaleffects were observed when eplerenone was administered to pregnant rats andrabbits during organogenesis at exposures 32 and 31 times, respectively thehuman exposure at the 100 mg/day therapeutic dose.

The estimated background risk of major birth defects andmiscarriage for the indicated population are unknown. In the US generalpopulation, the estimated background risk of major birth defects andmiscarriage in clinically recognized pregnancies is 2-4% and 15-20%,respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk forpre-eclampsia, gestational diabetes, premature delivery, and deliverycomplications (e.g., need for cesarean section, and post-partum hemorrhage).Hypertension increases the fetal risk for intrauterine growth restriction andintrauterine death. Pregnant women with hypertension should be carefullymonitored and managed accordingly.

Pregnant women with heart failure are at increased riskfor preterm birth. Stroke volume and heart rate increase during pregnancy,increasing cardiac output, especially during the first trimester. Clinicalclassification of heart disease may worsen with pregnancy and lead to maternaldeath. Closely monitor pregnant patients for destabilization of their heartfailure.

Data

Animal Data

Embryo-fetal development studies were conducted withdoses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures upto 32 and 31 times the human AUC for the 100 mg/day therapeutic dose,respectively) administered during organogenesis. No teratogenic effects wereseen in rats or rabbits, although decreased rat fetal weights were observed,and decreased body weight in maternal rabbits and increased rabbit fetalresorptions and post-implantation loss were observed at the highestadministered dosages.

In a pre-and postnatal development study pregnant ratswere administered eplerenone at doses up to 1000 mg/kg/day from Gestation Day 6through Lactation Day 20. Decreased pup weights were observed beginning atbirth at 1000 mg/kg/day.

Lactation

Risk Summary

There are no human data available on whether eplerenoneis present in human milk, or has effects on breastfed infants or on milkproduction. Eplerenone was present in the milk of lactating rats. When a drugis present in animal milk, it is likely that the drug will be present in humanmilk.

Females And Males Of Reproductive Potential

Infertility

Based on animal data, use of INSPRA may compromise malefertility. In mature rats, male fertility was decreased with eplerenoneexposure at 17 times the 100 mg/day human therapeutic dose. Reversibility ofeffects was not evaluated [see Nonclinical Toxicology].

Pediatric Use

In a 10-week study of 304 hypertensive pediatric patientsage 4 to 16 years treated with INSPRA up to 100 mg per day, doses that producedexposure similar to that in adults, INSPRA did not lower blood pressureeffectively. In this study and in a 1-year pediatric safety study in 149patients (age range 5 to 17 years), the incidence of reported adverse eventswas similar to that of adults.

INSPRA has not been studied in hypertensive patients lessthan 4 years old because the study in older pediatric patients did notdemonstrate effectiveness.

INSPRA has not been studied in pediatric patients withheart failure.

Geriatric Use

Heart Failure Post-Myocardial Infarction

Of the total number of patients in EPHESUS, 3340 (50%)were 65 and over, while 1326 (20%) were 75 and over. Patients greater than 75years did not appear to benefit from the use of INSPRA [see Clinical Studies].

No differences in overall incidence of adverse eventswere observed between elderly and younger patients. However, due to age-relateddecreases in creatinine clearance, the incidence of laboratory-documentedhyperkalemia was increased in patients 65 and older [see WARNINGS ANDPRECAUTIONS].

Hypertension

Of the total number of subjects in clinical hypertensionstudies of INSPRA, 1123 (23%) were 65 and over, while 212 (4%) were 75 andover. No overall differences in safety or effectiveness were observed betweenelderly subjects and younger subjects, however due to age-related decreases increatine clearance, the risk of hyperkalemia may be increased [see WARNINGSAND PRECAUTIONS].

Overdose Information for Inspra

No cases of human overdosage with eplerenone have beenreported. Lethality was not observed in mice, rats, or dogs after single oraldoses that provided Cmax exposures at least 25 times higher than in humansreceiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors ata Cmax 41 times the human therapeutic Cmax, progressing to sedation andconvulsions at higher exposures.

The most likely manifestation of human overdosage wouldbe anticipated to be hypotension or hyperkalemia. Eplerenone cannot be removedby hemodialysis. Eplerenone has been shown to bind extensively to charcoal. Ifsymptomatic hypotension should occur, supportive treatment should beinstituted. If hyperkalemia develops, standard treatment should be initiated.

Contraindications for Inspra

For All Patients

INSPRA is contraindicated in all patients with:

• serum potassium >5.5 mEq/L at initiation,
• creatinine clearance ≤30 mL/min, or
• concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

For Patients Treated For Hypertension

INSPRA is contraindicated for the treatment ofhypertension in patients with:

• type 2 diabetes with microalbuminuria,
• serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females,
• creatinine clearance <50 mL/min, or
• concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Clinical Pharmacology for Inspra

Mechanism Of Action

Eplerenone binds to the mineralocorticoid receptor andblocks the binding of aldosterone, a component of therenin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, whichoccurs primarily in the adrenal gland, is modulated by multiple factors,including angiotensin II and non-RAAS mediators such as adrenocorticotropichormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptorsin both epithelial (e.g., kidney) and nonepithelial (e.g., heart, bloodvessels, and brain) tissues and increases blood pressure through induction ofsodium reabsorption and possibly other mechanisms.

Eplerenone has been shown to produce sustained increasesin plasma renin and serum aldosterone, consistent with inhibition of thenegative regulatory feedback of aldosterone on renin secretion. The resultingincreased plasma renin activity and aldosterone circulating levels do notovercome the effects of eplerenone.

Eplerenone selectively binds to human mineralocorticoidreceptors relative to its binding to recombinant human glucocorticoid,progesterone, and androgen receptors.

Pharmacodynamics

There was no significant change in average heart rateamong patients treated with INSPRA in the combined clinical studies. Noconsistent effects of INSPRA on heart rate, QRS duration, or PR or QT intervalwere observed in 147 normal subjects evaluated for electrocardiographic changesduring pharmaco*kinetic studies.

Pharmaco*kinetics

Eplerenone is cleared predominantly by cytochrome P450(CYP) 3A4 metabolism, with an elimination half-life of 3 to 6 hours. Steadystate is reached within 2 days. Absorption is not affected by food. Inhibitorsof CYP3A (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone.

Absorption And Distribution

Mean peak plasma concentrations of eplerenone are reachedapproximately 1.5 to 2 hours following oral administration. Absorption is notaffected by food.The absolute bioavailability of eplerenone is 69% followingadministration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and areaunder the curve (AUC) are dose proportional for doses of 25 mg to 100 mg andless than proportional at doses above 100 mg. Upon repeat dosing, steady statelevels are reached within 2 days.

The plasma protein binding of eplerenone is about 50% andit is primarily bound to alpha 1-acid glycoproteins. The apparent volume ofdistribution at steady state ranged from 42 to 90 L. Eplerenone does notpreferentially bind to red blood cells.

Metabolism And Excretion

Eplerenone metabolism is primarily mediated via CYP3A4.No active metabolites of eplerenone have been identified in human plasma.

Less than 5% of an eplerenone dose is recovered asunchanged drug in the urine and feces. Following a single oral dose ofradiolabeled drug, approximately 32% of the dose was excreted in the feces andapproximately 67% was excreted in the urine. The elimination half-life ofeplerenone is approximately 3 to 6 hours. The apparent plasma clearance isapproximately 10 L/hr.

Age, Gender, And Race

The pharmaco*kinetics of eplerenone at a dose of 100 mgonce daily has been investigated in the elderly (≥65 years), in males andfemales, and in Blacks. At steady state, elderly subjects had increases in Cmax(22%) and AUC (45%) compared with younger subjects (18 to 45 years). Thepharmaco*kinetics of eplerenone did not differ significantly between males andfemales. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks [seeDOSAGE AND ADMINISTRATION and Use In Specific Populations].

Renal Impairment

The pharmaco*kinetics of eplerenone was evaluated inpatients with varying degrees of renal impairment and in patients undergoinghemodialysis. Compared with control subjects, steady state AUC and Cmax wereincreased by 38% and 24%, respectively, in patients with severe renalimpairment and were decreased by 26% and 3%, respectively, in patientsundergoing hemodialysis. No correlation was observed between plasma clearanceof eplerenone and creatinine clearance. Eplerenone is not removed byhemodialysis [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

The pharmaco*kinetics of eplerenone 400 mg has beeninvestigated in patients with moderate (Child-Pugh Class B) hepatic impairmentand compared with normal subjects. Steady state Cmax and AUC of eplerenone wereincreased by 3.6% and 42%, respectively.

Heart Failure

The pharmaco*kinetics of eplerenone 50 mg was evaluated in8 patients with heart failure (NYHA classification II–IV) and 8 matched(gender, age, weight) healthy controls. Compared with the controls, steadystate AUC and Cmax in patients with stable heart failure were 38% and 30%higher, respectively.

Drug-Drug Interactions

Eplerenone is metabolized primarily by CYP3A4. Inhibitorsof CYP3A cause increased exposure [see DRUG INTERACTIONS].

Drug-drug interaction studies were conducted with a 100mg dose of eplerenone.

Following a single dose of INSPRA 100 mg and CYP3Ainhibitor ketoconazole 200 mg twice a day, eplerone's Cmax was 1.7-fold and AUCwas 5.4-fold compared with eplerone alone.

Administration of eplerenone with moderate CYP3A inhibitors(e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mgthree times a day, fluconazole 200 mg once daily) resulted in increases in Cmaxof eplerenone ranging from 40% to 60% and AUC from 100% to 190%.

Grapefruit juice caused a 25% increase in exposure.

Eplerenone is not an inhibitor of CYP1A2, CYP3A4,CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism ofamiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone,dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan,lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol,midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide,triazolam, verapamil, or warfarin in vitro. Eplerenone is not a substrate or aninhibitor of P-Glycoprotein at clinically relevant doses.

No clinically significant drug-drug pharmaco*kineticinteractions were observed when eplerenone was administered with cisapride,cyclosporine, digoxin, glyburide, midazolam, oral contraceptives(norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John's wort (aCYP3A inducer) caused a small (about 30%) decrease in eplerenone AUC.

No significant changes in eplerenone pharmaco*kineticswere observed when eplerenone was administered with aluminum-andmagnesium-containing antacids.

Clinical Studies

Heart Failure Post-Myocardial Infarction

The eplerenone post-acute myocardial infarction heartfailure efficacy and survival study (EPHESUS) was a multinational, multicenter,double-blind, randomized, placebo-controlled study in patients clinicallystable 3 to 14 days after an acute MI with LV dysfunction (as measured by leftventricular ejection fraction [LVEF] ≤40%) and either diabetes orclinical evidence of HF (pulmonary congestion by exam or chest x-ray or S3).Patients with HF of valvular or congenital etiology, patients with unstablepost-infarct angina, and patients with serum potassium >5.0 mEq/L or serumcreatinine >2.5 mg/dL were to be excluded. Patients were allowed to receivestandard post-MI drug therapy and to undergo revascularization by angioplastyor coronary artery bypass graft surgery.

Patients randomized to INSPRA were given an initial doseof 25 mg once daily and titrated to the target dose of 50 mg once daily after 4weeks if serum potassium was <5.0 mEq/L. Dosage was reduced or suspendedanytime during the study if serum potassium levels were ≥5.5 mEq/L [see DOSAGEAND ADMINISTRATION].

EPHESUS randomized 6,632 patients (9.3% U.S.) at 671centers in 27 countries. The study population was primarily white (90%, with 1%Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64years (range, 22 to 94 years). The majority of patients had pulmonarycongestion (75%) by exam or x-ray and were Killip Class II (64%). The meanejection fraction was 33%. The average time to enrollment was 7 days post-MI.Medical histories prior to the index MI included hypertension (60%), coronaryartery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%),previous MI (27%), and HF (15%).

The mean dose of INSPRA was 43 mg/day. Patients alsoreceived standard care including aspirin (92%), ACE inhibitors (90%),beta-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductaseinhibitors (60%).

Patients were followed for an average of 16 months(range, 0 to 33 months). The ascertainment rate for vital status was 99.7%.

The co-primary endpoints for EPHESUS were (1) the time todeath from any cause, and (2) the time to first occurrence of eithercardiovascular mortality [defined as sudden cardiac death or death due toprogression of HF, stroke, or other CV causes] or CV hospitalization (definedas hospitalization for progression of HF, ventricular arrhythmias, acute MI, orstroke).

For the co-primary endpoint for death from any cause,there were 478 deaths in the INSPRA group (14.4%) and 554 deaths in the placebogroup (16.7%). The risk of death with INSPRA was reduced by 15% [hazard ratioequal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log ranktest)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 andthe components of mortality are provided in Table 5.

Figure 1: Kaplan-Meier Estimates of All-CauseMortality

Table 5: Components of All-Cause Mortality in EPHESUS

Most CV deaths were attributed to sudden death, acute MI,and HF.

The time to first event for the co-primary endpoint of CVdeath or hospitalization, as defined above, was longer in the INSPRA group(hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). Ananalysis that included the time to first occurrence of CV mortality and all CVhospitalizations (atrial arrhythmia, angina, CV procedures, progression of HF,MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effectwith a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028).The combined endpoints, including combined all-cause hospitalization andmortality were driven primarily by CV mortality. The combined endpoints inEPHESUS, including all-cause hospitalization and all-cause mortality, arepresented in Table 6.

Table 6: Rates of Death or Hospitalization in EPHESUS

Mortality hazard ratios varied for some subgroups asshown in Figure 2. Mortality hazard ratios appeared favorable for INSPRA forboth genders and for all races or ethnic groups, although the numbers ofnon-Caucasians were low (648, 10%). Patients with diabetes without clinicalevidence of HF and patients greater than 75 years did not appear to benefitfrom the use of INSPRA. Such subgroup analyses must be interpreted cautiously.

Figure 2: Hazard Ratios of All-Cause Mortality bySubgroups

Analyses conducted for a variety of CV biomarkers did notconfirm a mechanism of action by which mortality was reduced.

Hypertension

The safety and efficacy of INSPRA have been evaluatedalone and in combination with other antihypertensive agents in clinical studiesof 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and22% elderly (age ≥65). The studies excluded patients with elevatedbaseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine(generally >1.5 mg/dL in males and >1.3 mg/dL in females).

Two fixed-dose, placebo-controlled, 8-to 12-weekmonotherapy studies in patients with baseline diastolic blood pressures of 95to 114 mm Hg were conducted to assess the antihypertensive effect of INSPRA. Inthese two studies, 611 patients were randomized to INSPRA and 140 patients toplacebo. Patients received INSPRA in doses of 25 mg to 400 mg daily as either asingle daily dose or divided into two daily doses. The mean placebo-subtractedreductions in trough cuff blood pressure achieved by INSPRA in these studies atdoses up to 200 mg are shown in Figures 3 and 4.

Figure 3: INSPRA Dose Response - Trough Cuff SBPPlacebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

Figure 4: INSPRA Dose Response - Trough Cuff DBPPlacebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

Patients treated with INSPRA 50 mg to 200 mg dailyexperienced significant decreases in sitting systolic and diastolic bloodpressure at trough with differences from placebo of 6–13 mm Hg (systolic) and3–7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hourambulatory blood pressure monitoring (ABPM). In these studies, assessments of24-hour ABPM data demonstrated that INSPRA, administered once or twice daily,maintained antihypertensive efficacy over the entire dosing interval. However,at a total daily dose of 100 mg, INSPRA administered as 50 mg twice per dayproduced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressurereductions than 100 mg given once daily.

Blood pressure lowering was apparent within 2 weeks fromthe start of therapy with INSPRA, with maximal antihypertensive effectsachieved within 4 weeks. Stopping INSPRA following treatment for 8 to 24 weeksin six studies did not lead to adverse event rates in the week followingwithdrawal of INSPRA greater than following placebo or active controlwithdrawal. Blood pressures in patients not taking other antihypertensives rose1 week after withdrawal of INSPRA by about 6/3 mm Hg, suggesting that the antihypertensiveeffect of INSPRA was maintained through 8 to 24 weeks.

Blood pressure reductions with INSPRA in the twofixed-dose monotherapy studies and other studies using titrated doses, as wellas concomitant treatments, were not significantly different when analyzed byage, gender, or race with one exception. In a study in patients with low reninhypertension, blood pressure reductions in Blacks were smaller than those inwhites during the initial titration period with INSPRA.

INSPRA has been studied concomitantly with treatment withACE inhibitors, ARB, calcium channel blockers, beta-blockers, andhydrochlorothiazide. When administered concomitantly with one of these drugsINSPRA usually produced its expected antihypertensive effects.

Patient Information for Inspra

Advise patients receiving INSPRA:

Not to use potassium supplements or salt substitutescontaining potassium without consulting the prescribing physician [see WARNINGSAND PRECAUTIONS].

To call their physician if they experience dizziness,diarrhea, vomiting, rapid or irregular heartbeat, lower extremity edema, ordifficulty breathing [see WARNINGS AND PRECAUTIONS].